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1 The Role of the Various Monocyte Types in Atherothrombotic Disease Protective vs. Detrimental Effects and Therapeutic Implications Matthias Nahrendorf MGH Center for Systems Biology HARVARD MEDICAL SCHOOL
2 Healing following myocardial infarction matters Good healing MedicineNet.com Good prognosis Bad healing Circulation Mar;87(3): % chance of death in next
3 Monocyte/macrophage heterogeneity in myocardial infarction Swirski & Nahrendorf, Science 213;339:161-6
4 Monocytes/macrophages in atherosclerosis Swirski & Nahrendorf, Science 213;339:161-6
5 Impaired infarct healing after plaque rupture Atherosclerosis Blood monocytosis Recruitment Ly-6C hi Inflammatory cyto/chemokines (e.g. MPO, TNF-α) Protease activity (e.g. MMPs, cathepsins) Resolution of inflammation (e.g. reduced TGF-β) Infarct expansion LV dilation EF Collagen synthesis Heart Failure Circulation 21; 121:2437
6 Quality of healing Is there a window of therapeutic opportunity to intervene on inflammation post? vertex (coronary ligation in healthy wild-type mice) 3 patients on steroids 4 patients with high CD14 + CD16 blood levels 5 monocyte depleted mice 2,3 patients with blood monocytosis 6 splenectomized mice 1 apoe -/- with blood monocytosis 7 Inflammatory monocytes 1. Swirski & Nahrendorf, Science van Amerongen, Am J Pathol Nahrendorf & Swirski, JEM Roberts, Circulation Tsujioka, JACC Maekawa, JACC Panizzi, JACC 29 Circulation 21; 121:2437
7 Mortality (%) White blood cell count associates with in-hospital mortality in infarct patients (n = 115,) Leukocyte count Coller et al., ATVB 25;25:658-67
8 No d1 d3 d5 d7 % of BrdU + HSC SUV Bone marrow Blood Spleen Destination tissue Long-term hematopoietic stem cell Short-term hematopoietic stem cell Common myeloid progenitor Granulocyte Macrophage progenitor Macrophage dendritic cell progenitor Monocyte Macrophage 18 No FACS Bone Marrow. 18 F-FLT PET No Dutta et al., Cell Stem Cell 215
9 no Ly-6C hi monocytes/mg tissue (1 4 ) Monocytes in Spleen The spleen is a reservoir for monocytes after Organization Expression profile Behavioral activity vessel parenchyma splenic monocytes cluster in the subcapsular red pulp Monocytes in Blood splenic monocytes resemble blood monocytes (99.998%) Pre injury Post injury Inflammation mobilizes monocytes in vivo Release Relocation Consequence 6 Pre + Spleen Spleen + Spleen Spleen 3 Ang II triggers release of monocytes into peripheral blood Before After.5 1 Day post The spleen contributes monocytes in infarct Released splenic monocytes participate in inflammation Science 29; 325:612
10 No Increase in protease activity (pmol) Ex vivo TBR FRI enhances protease activity in plaque Week Week 3 Week No Dutta/Courties et al., Nature 212;487:325-9
11 Ly-6C high monocytes (1 3 ) / aorta Plaque size (mm 2 ) CD11b + area (mm 2 ) enhances monocyte/macrophage numbers in plaque No 6 3 No Age (in weeks) Dutta/Courties et al., Nature 212;487:325-9
12 enhances atherosclerosis Swirski & Nahrendorf, Science 213;339:161-6
13 18 F-FDG uptake increases in atheroma, bone marrow, and spleen during acute Tawakol et al., ijacc 215
14 BrdU steady state non-infarcted parabiont non-infarcted parabiont CD48 % of BrdU + HSCs/femur C-kit Heart IL-1β mrna Infarct IL-1β (pg/ml) Blood IL-1β (pg/ml) Marrow IL-1β (pg/ml) Sager / Dutta Danger signals: IL-1β no 24h 72h no 24h 72h no 24h 72h no 24h 72h steady state non-infarcted parabiont non-infarcted IL1R1 -/- parabiont 14d 3 days FACS 24 Sca-1 14d 3 days FACS 12 IL1R1 -/- CD15 IL1R1 -/- 14d IL1R1 -/- 3 days FACS CD15
15 BrdU % of BrdU+ HSCs/femur CD HSCs/femur C-kit 1 4 LSKs/femur Anti IL-1β therapy modulates hematopoiesis no + Ctrl IgG.54 + Ctrl IgG anti IL-1β Sca CD Sca-1 Sager / Dutta
16 F4/8 Ly6c high monocytes (x1 3 )/mg infarct Ly6c low monocytes (x1 3 )/mg infarct Lineage neutrophils (x1 3 )/mg infarct macrophages (x1 3 )/mg infarct Anti IL-1β therapy mutes inflammatory leukocytes during myocardial infarction + Ctrl IgG + anti IL-1β CD11b Ly6C Sager / Dutta
17 21 d after decrease in LVEF (%) 7 d after infarct protease activity (pmol) 1 d after infarct size (% of myocardium) Anti IL-1β therapy improves LV function post + Ctrl IgG + anti IL-1β Sager / Tricot / Wojtkiewicz
18 Acknowledgements Fil Swirski Dan Anderson Chares Lin David Scadden Marcelo Di Carli David Sosnovik Ahmed Tawakol Willem Mulder Zahi Fayad Michael Moskowitz Ralph Weissleder Peter Libby Ned Keliher Maulik Majmudar Gabriel Courties Florian Leuschner Partha Dutta Hendrik Sager Felix Hoyer Gabriel Courties Fanny Herrison Yuxiang Ye Yoshiko Iwamoto Yuan Sun Kamila Naxerova csb.mgh.harvard.edu/nahrendorf HHSN C, R1HL95629, R1HL96576, R1HL114477, R1HL HARVARD MEDICAL SCHOOL
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